Alzheimer's disease (AD) is the most frequent cause of dementia in the United States and is currently the fourth most common cause of death. The disease can strike persons as young as 40-50 years of age and affects over three million individuals. The origin of the disease is unknown, and because the presence of the disease is difficult to determine without invasive biopsy, its time of onset is unknown. The condition is characterized by impairments in memory, cognition, language and mobility, and these conditions become progressively more severe with time. Neuropathological examination of the brains of affected individuals discloses the presence of several characteristic abnormalities: neuritic plaques consisting of abnormal neuronal axon terminals associated with a core of extra-cellular amyloid protein; neurofibrillary tangles comprised of bundles of cross-linked protein filaments which have accumulated in the neuronal cell bodies; and granulovacuolar degeneration which consists of intercellular vacuoles present mostly in hippocampal pyramidal neurons.
In addition, a strong correlation has been found between the density of amyloid-containing plaques in the cortex of AD victims at autopsy and the severity of their cognitive defects. Until recently, diagnosis of AD was based on clinical criteria involving clinical diagnosis of physical and mental impairment and determination that other diseases with the same characteristics were not the cause of the impairments.
Post-mortem slices of brain tissue of victims of Alzheimer's disease have been shown to exhibit the presence of amyloid (an amorphous mixture of protein, carbohydrate and lipid complexes) in the form of proteinaceous extracellular cores of the neuritic plaques characteristic of the disease. The amyloid cores of such senile plaques are composed of microscopic fibrils whose protein is arranged in a predominately .beta.-pleated sheet configuration. AD plaque amyloid appears to contain one or more characteristic protein constituents, and some have been isolated and purified. Vascular deposits of amyloid fibrils in non-Alzheimer's amyloidoses have been shown to be derived from an abnormal serum protein by Glenner, G. New Eng.J.Med. 302:1283-1291 (1980). The genetic locus for the amyloid protein has been localized to chromosome 21 as reported by George-Hyslop et al, Science. 235:885-890 (1987) and Tanzi et al, Science. 235:880-884 (1987). Isolation and partial sequencing of the gene has been reported by Goldaber et al, Science. 235:877-880 (1987), and partial sequencing of at least one of the amyloid AD proteins has been reported by Glenner, G. et al, Biochemical and Biophysical Communications. 120:885-890 (1984).
More recently, immunoassay methods have been developed for detecting the presence of neurochemical markers in AD patients and to detect an AD related amyloid protein in cerebral spinal fluid as summarized by Warner, M. Anal. Chem. 59:1203A-1204A (1987). These new methods, while being a major advance over the earlier method for diagnosing AD, have not proven to detect AD in all patients, particularly at early stages of the disease.
Because Alzheimer's disease is slow in onset, can first appear as early as the fifth decade of life, and is progressive in nature, the efficiency of a cure could critically depend upon early detection. Additionally, the value of any new therapy in alleviating or curing the disease could be better ascertained if a rapid, safe and effective diagnostic procedure were available to monitor the progress of AD patients following treatment.
The most advanced diagnostic tests for AD detection developed to date determine the AD-associated amyloid protein in spinal fluid using an antibody binding selectively therewith. A spinal tap procedure is required to obtain a sample for testing. Such a procedure is painful, invasive, potentially dangerous, costly, and the patient often must be hospitalized overnight for observation.
Cerebrovascular amyloidosis has been observed only in patients with Alzheimer's disease and adult Down's syndrome by Glenner, G., COLD SPRING HARBOR SYMPOSIUM. pp 137-144 (1983) and a familial Icelandic cerebrovascular amyloidosis syndrome by Cohen, et al, J.Exp.Med. 158:623-628 (1983). The latter conditions have characteristics other than dementia which are easily determined and can be distinguished from AD. Amyloid thus can be used as a chemical marker for the disease.
Non-cerebral amyloid is an extracellular, amorphous, eosinophilic material most commonly arising as a consequence of chronic inflammatory disease of long standing. Spleen, liver, kidneys, adrenals, lymph nodes and pancreas are the organs usually affected. Gratuitously, amyloid of this type was referred to as secondary or typical. Primary, or atypical amyloid is usually found in muscle and the cardiovascular system, but may be more conveniently diagnosed in rectal, skin or gingival biopsies. It arises in the absence of any obvious predisposing inflammatory disease.